This invention is directed to a method for use of a carbamate compound in preventing or treating movement disorders. More particularly, this invention is directed to a method for use of halogenated 2-phenyl-1,2-ethanediol monocarbamate or dicarbamate compounds for preventing or treating movement disorders.
Movement disorders are a broad group of disorders without a single underlying cause, resulting from a variety of neurological dysfunctions directly or indirectly linked to neuronal damage or abnormalities in nervous system pathways (Blandini F, et. al., Movement disorders, Princ. Neural. Aging, 1997, 441-453; Koller W C, et. al., Pharmacologic treatment of essential tremor, Neurology, 2000, 54 (11, Suppl. 4), S30-S38; Gasser T, et. al., Genetics of Parkinson""s disease and other movement disorders, Neurogenetics, 2000, 351-372; Collado-Seidel V, et. al., Aetiology and treatment of restless legs syndrome, CNS Drugs, 1999, 12 (1), 9-20; Bucher S F, et. al., Cerebral generators involved in the pathogenesis of the restless legs syndrome, Annals of Neurology, 1997, 41 (5), 639-45; Kanazawa I, Extrapyramidal tract symptoms in degenerative diseases. Involuntary movement in degenerative diseases. Huntington""s disease, chorea-acanthocytosis and benign hereditary chorea. Saishin Naikagaku Taikei, 1997, 68, 156-163; Scheidt C E, Psychosomatic aspects of idiopathic spasmodic torticollis. Results of a multicenter study. Psychotherapie, Psychosomatik, Medizinische Psychologie, 1998, 48 (1), 1-12; Caligiuri M P, Antipsychotic-induced movement disorders in the elderly: epidemiology and treatment recommendations, Drugs Aging, 2000, 17 (5), 363-384; Poewe W, What is new in movement disorders, Wien. Klin. Wochenschr., 1999, 111 (17), 664-671; Klein C, et. al., Evaluation of the role of the D2 dopamine receptor in myoclonus dystonia, Ann. Neurol., 2000, 47 (3), 369-373).
Such movement disorders include, but are not limited to, benign essential tremor (ET), tremor in Parkinson""s disease (PD) and Parkinsonism, other non-related ET or PD tremors (such as head/limb resting, simple kinetic and intention, postural-associated, position-associated, orthostatic, enhanced physiologic, psychogenic, task-associated, voice, cerebellar, rubral and other central and non-classical tremors), restless leg syndrome (RLS), restless arm syndrome (RAS), chorea in Huntington""s disease, idiopathic torsion dystonia, focal torsion dystonia, myoclonus, athetosis, abnormal movements in Wilson""s disease, Gilles de La Tourette""s syndrome, paroxysmal movement disorders (including paroxysmal dystonia (eg, kinesgenic paroxystic choreoathetosis, dystonic paroxystic choreoathetosis, intermediate paroxystic choreoathetosis and nocturnal paroxystic choreoathetosis), paroxystic ataxia and paroxystic tremor), post-anoxic spasms, post-spinal cord injury spasms, multiple sclerosis-associated tremor and drug-induced tremors and movement disorders (including, and not limited to, postural tremor, acute dystonia, chorea, akathisia, tardive dyskinesia and Parkinson""s-like syndromes).
Antiepileptic drugs have been used to treat a variety of nonepileptic conditions including movement disorders (Ettore B, The use of anticonvulsants in neurological conditions other than epilepsy: A review of the evidence from randomized controlled trials, CNS Drugs, 1999, 11 (1), 61-82). Essential tremor is a common disorder with oscillating movements that often causes functional disability, potentially leading to physiological and emotional difficulties. Its prevalence is about 3.5-55 per 1000 population (Tanner C M, Epidemiology of Movement disorders. In: Anderson D W editor. Neuroepidemiology, CRC Press, 1991, 193-216). Beta-receptor blocking agents (propranolol and analogues) are a line of therapy for essential tremor (Iwata S, et. al., Effects of beta-adrenergic blockers on drug-induced tremors, Biochem. Behav., 1993, 44 (3), 611-13). However, in addition to the incomplete clinical response, beta-receptor blocking agents are contraindicated in asthma, heart block, or congestive heart failure and must be used judiciously in patients with diabetes mellitus or recurrent depression.
In various conditions, anticonvulsants (such as carbamazepine, gabapentin and topiramate) may be effective in treating essential tremor. Topiramate given to nine patients with essential tremor may be useful for the management of essential tremor, especially in patients partially responsive to other established forms of treatment (Galvez-Jimenez N and Hargreave M, Topiramate and essential tremor, Ann. Neurol, 2000, 47 (6), 837-838). Eight patients rated themselves as better and with less disability after topiramate therapy. One patient reported increased diuresis while receiving topiramate. The most common side effects were fatigue and paresthesias. Gabapentin, an antiepileptic, has been used for treating essential tremor (Koller W C, Pharmacologic treatment of essential tremor, Neurology, 2000, 54 (11), (Suppl. 4), S30-S38). In an open-label report, gabapentin reduced tremor in five patients. Three of the patients elected to remain on gabapentin as opposed to their previous medication. Carbamazepine and gabapentin have shown effectiveness in treating essential tremor (Ettore B, The use of anticonvulsants in neurological conditions other than epilepsy: A review of the evidence from randomized controlled trials, CNS Drugs, 1999, 11 (1), 61-82). Other anticonvulsants may also be effective in treating essential tremor (Koller W C, Pharmacologic treatment of essential tremor, Neurology, 2000, 54 (11), (Suppl. 4), S30-S38; Gorman W P, et. al., A comparison of primidone, propranolol in essential tremor, using quantitative analysis, J. Neurol. Neurosurg. Psychiatry, 1986; 49, 64-68; Gironell A, et. Al., A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor, Arch. Neurol., 1999, 56, 475; Leslie M, Nonepileptic uses of gabapentin, Epilepsia, 1999, 40 (Suppl. 6), S66-S72; 837-838; Ettore B, The use of anticonvulsants in neurological conditions other than epilepsy: A review of the evidence from randomized controlled trials, CNS Drugs, 1999, 11 (1), 61-82).
RLS and RAS are common, chronic disorders characterized by a need to move the legs or arms, especially when relaxed. These neurological movement disorders also affect induction of sleep and can become a significant source of sleep-disturbance because of the compulsive movement of the extremities; such disorders and consequences can also be associated with paresthesias and excessive daytime tiredness. There is 1-5% prevalence of these disorders in the general population and 15% in the medical population. The etiology of RLS remains unknown. Levodopa/decarboxylase inhibitors (carbidopa, benserazide) and dopamine agonists are regarded as a line of treatment for RLS. The development of time shift and/or augmentation of symptoms is a major problem with dopaminergic treatment. Importantly, anticonvulsants such as gabapentin and carbamazepine also have efficacy in RLS (Adler C H, Treatment of restless legs syndrome with gabapentin, Clin. Neuropharmacol., 1997, 20 (2), 148-151; Merren M D, Gabapentin for treatment of pain and tremor: a large case series, South Med. J., 1998 Aug, 91 (8), 739-44; Wetter T C, Pollmacher T, Restless legs and periodic leg movements in sleep syndromes, J. Neurol, 1997 Apr, 244 (4 Suppl 1), S37-45). The efficacy of anticonvulsants in movement disorders such as essential tremor and RLS is thought to be due, in part, to the neurostabilizing properties of this class of drugs, which may restore the imbalance in the generation and transmission of motor impulses.
Substituted phenyl alkyl carbamate compounds have been described in U.S. Pat. No. 3,265,728 to Bossinger, et al (hereby incorporated by reference), as useful in treating the central nervous system, having tranquilization, sedation and muscle relaxation properties of the formula: 
wherein R1 is either carbamate or alkyl carbamate containing from 1 to 3 carbon atoms in the alkyl group; R2 is either hydrogen, hydroxy, alkyl or hydroxy alkyl containing from 1 to 2 carbons; R3 is either hydrogen or alkyl containing from 1 to 2 carbons; and X can be halogen, methyl, methoxy, phenyl, nitro or amino.
A method for inducing calming and muscle relaxation with carbamates has been described in U.S. Pat. No. 3,313,692 to Bossinger, et al (hereby incorporated by reference) by administering a compound of the formula: 
in which W represents an aliphatic radical containing less than 4 carbon atoms, wherein R1 represents an aromatic radical, R2 represents hydrogen or an alkyl radical containing less than 4 carbon atoms, and X represents hydrogen or hydroxy or alkoxy and alkyl radicals containing less than 4 carbon atoms or the radical: 
in which B represents an organic amine radical of the group consisting of heterocyclic, ureido and hydrazino radicals and the radical xe2x80x94N(R3)2 wherein R3 represents hydrogen or an alkyl radical containing less than 4 carbon atoms.
Optically pure forms of halogen substituted 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates have also been described in U.S. Pat. No. 6,103,759 to Choi, et al (hereby incorporated by reference), as effective for treating and preventing central nervous system disorders including convulsions, epilepsy, stroke and muscle spasm; and as useful in the treatment of central nervous system diseases, particularly as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants, of the formulae: 
wherein one enantiomer predominates and wherein the phenyl ring is substituted at X with one to five halogen atoms selected from fluorine, chlorine, bromine or iodine atoms and R1, R2 , R3, R4, R5 and R6 are each selected from hydrogen and straight or branched alkyl groups with one to four carbons optionally substituted with a phenyl group with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, amino, nitro and cyano. Pure enantiomeric forms and enantiomeric mixtures were described wherein one of the enantiomers predominates in the mixture for the compounds represented by the formulae above; preferably one of the enantiomers predominates to the extent of about 90% or greater; and, most preferably, about 98% or greater.
Halogen substituted 2-phenyl-1,2-ethanediol carbamate compounds of Formula (I) or Formula (II) have not been previously described as useful for preventing or treating movement disorders. Recent preclinical studies have revealed previously unrecognized pharmacological properties which suggest that a compound of Formula (I) or Formula (II) is useful in preventing or treating movement disorders. Therefore, it is an object of the present invention to teach a method for use of a compound of Formula (I) or Formula (II) in preventing or treating movement disorders.
The present invention is directed to a method for preventing or treating movement disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of Formula (I) and Formula (II): 
wherein
phenyl is substituted at X with one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine; and,
R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and C1-C4 alkyl; wherein C1-C4 alkyl is optionally substituted with phenyl (wherein phenyl is optionally substituted with substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, nitro and cyano).
Embodiments of the invention include a method for preventing or treating movement disorders comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of Formula (I) and Formula (II).
Embodiments of the invention include the use of a compound selected from the group consisting of Formula (I) and Formula (II) for the preparation of a medicament for preventing or treating movement disorders in a subject in need thereof.
Embodiments of the method include the use of an enantiomer selected from the group consisting of Formula (I) and Formula (II) or enantiomeric mixture wherein one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates. For enantiomeric mixtures wherein one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates, preferably, one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the extent of about 90% or greater. More preferably, one enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the extent of about 98% or greater.